Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the biosynthesis of cholesterol, fatty acid, and triglyceride. They control the expression of crucial genes involved in lipogenesis and uptake. Inhibition of the SREBP pathway can reduce lipid biosynthesis and thus can be a strategy to treat metabolic diseases, such as type II diabetes, insulin resistance, fatty liver and atherosclerosis [Xiao, et al. Acta Biochim. Biophys. Sin (2013) 45:1, pp 2-10]. In mammals, three SREBP isoforms are known, designated SREBP-1a, SREBP-1c, and SREBP-2. SREBP-1a controls a broad range of SREBP targets including production of fatty acids, triglycerides, phospholipids and cholesterol. SREBP-1c preferentially activates genes of fatty acid and triglyceride metabolism, whereas SREBP-2 preferentially activates genes of cholesterol metabolism, both of which have been studied in human and mice models [Horton, et al. J. Clin. Invest. (2002) 109:9, pp 1125-1131], as well as Drosophila [Rawson. Nature Rev. Mol. Cell Biol. (2003) 4:8, pp 631-640].
Recent studies have also presented a link between upregulation of lipid synthesis and prostate cancer [Suburu, et al. Prostaglandins Other Lipid Mediat. (2012) 98:0, pp 1-10]. The metabolic shift from catabolic to anabolic metabolism is a hallmark of cancer cells. Many cancers require synthesis of fatty acids, and other lipids such as cholesterol and androgens are implicated in prostate cancer. SREBP-1c is the major transcriptional regulator of enzymes in the fatty acid synthesis pathway, and its expression can be stimulated by androgens and epidermal growth factor (EGF) in prostate cancer cells. Overexpression of SREBP-1c is sufficient to cause tumorigenicity and invasion of prostate cancer cells. SREBP-1 can also increase expression of NOX5, a prominent producer of reactive oxygen species (ROS) and regulator of prostate cancer cell growth [Brar, et al. Am. J. Physiol. Cell Physiol. (2003) 285:2, pp C353-369; Huang, et al. Mol. Cancer Res. (2012) 10:1, pp 133-142; Huang, et al. Cancer Research (2012) 72:8, SUPPL. 1; Huang, et al. Mol. Cancer Res. (2014) 13:4, pp 855-866].
SREBP-2, a regulator of androgen synthesis, is also itself regulated by androgens, demonstrating a direct feedback circuit for regulation of androgen production. SREBP-2 expression increases during disease progression and is significantly higher after castration. This transcription factor also lacks its feedback inhibition in prostate cancer cells, implicating a role for cholesterol and androgen synthesis in prostate cancer [Eberle, et al. Biochimie (2004) 86:11, pp 839-848; Ettinger, et al. Cancer Res. (2004), 64:6, pp 2212-2221; Chen, et al. Int. J. Cancer (2001), 91:1, pp 41-45].
Blocking SREBP functions linked to disease states therefore represents an important therapeutic approach for limiting lipid/cholesterol synthesis in membrane production which occurs in metabolic diseases and in cancer progression, as well as in viral pathogenesis [Naar, et al. Clin. Lipidol. (2012) 7:1, pp 27-36]. Small molecule therapeutics affecting metabolic regulators such as mTOR, AMPK or SIRT1, including Rapamycin, Metformin, or Resveratrol, respectively, may impinge on the transcriptional activity of SREBPs. Recently, two non-sterol small molecules, fatostatin and betulin have been found to inhibit SREBP processing [Kamisuki, et al. Chem. Biol. (2009) 16:8, pp 882-892; Tang, et al. Cell. Metab. (2011) 13:1, pp 44-56]. Methods for the treatment of cancers having a p53 mutation, such as breast cancer cells, using SREBP inhibitors have been presented [Freed-Pastor, et al. PCT. Publication WO2013-110007A1].
Fatostatin analogs have recently been described as potential therapeutics for the treatment of metabolic disorders [Uesugi, et al. U.S. Pat. No. 8,207,196]. Key compounds presented therein are based around Formula X:
wherein R is H, F, Cl, Br, OBz, OH, OCH3, OCH2CO2Me, OCH2CO2H, NH2, NHiPr, NHCOCH3, NHSO2Me, NH[benzyl], NH[cyclopropyl], NH[tertbutyloxycarbonyl], NH[cyclohexyl], NH[tosyl], NH[quinolin-8-yl], and NH[thiophen-2-yl]. In particular, one compound (FGH10019), the methanesulfonamide derivative of fatostatin above wherein R is NHSO2Me, has been described as a lead candidate [Kamisuki, et al. J. Med. Chem. (2011) 54:13, pp 4923-4927].